Ultrasound-triggered delivery of siRNA as treatment for diabetic kidney disease

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: 2R44DK083142-02A1
Agency Tracking Number: R44DK083142
Amount: $1,338,742.00
Phase: Phase II
Program: SBIR
Awards Year: 2011
Solicitation Year: 2011
Solicitation Topic Code: NIDDK
Solicitation Number: PA10-050
Small Business Information
DUNS: 006662785
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 (877) 290-4043
Business Contact
Phone: (858) 427-3675
Email: joshua.rychak@targeson.com
Research Institution
DESCRIPTION (provided by applicant): Gene therapy in the context of diabetic kidney disease holds tremendous promise, although concrete progress in the field has been difficult to achieve. Specifically, the growth factor TGF-2 is known to play a critical role in glomerular matrix expansion and progression of glomerular fibrosis, and inhibition of TGF-2 activity by neutralizing antibodies has shown striking efficacy in several animal models of diabetic kidney disease. However, as is the case with many targets of molecular therapy, TGF-2 is strongly implicated in numerous somatic processes, and off-target inhibition may pose severe detrimental effects. Means by which TGF-2 therapy could be targeted specifically to the impaired kidney could offer a critical breakthrough in making gene therapy for kidney disease a reality. In the current proposal, we aim to develop a novel microbubble-based delivery vehicle for targeted TGF-2 gene therapy. We have developed a microbubble that can be conjugated with a payload of plasmid or siRNA, and targeted to the diabetic kidney by means of a selectin-binding targeting ligand. These agents can be administered intravenously, and their accumulation within the kidney monitored by non-invasive ultrasound imaging. Release of the siRNA payload and transfer into the targeted glomerular cells is mediated by application of high-power ultrasound energy specifically to the kidneys, which causes rapid destruction of the microbubbles and a transient poration of the adjacent cells. Remaining untargeted agents are cleared to the liver, spleen, and lung, where agent destruction by deflation exposes any residual siRNA to endogenous nucleases, thus potentially reducing off-target effects. We aim to evaluate this targeted siRNA delivery strategy inseveral clinically-relevant mouse models of diabetes. TGF-2 knock-down, and reduction in mesangial matrix expansion, will be assessed longitudinally. We will also systematically assess the payload capacity and stability of the agent, and evaluate toxicityand biodistribution in rodents. We anticipate that successful completion of the proposed aims will demonstrate efficacy of this targeted delivery technology for treatment of diabetic kidney disease, and provide Targeson with critical data needed to advanceto the next stage of development for clinical use. PUBLIC HEALTH RELEVANCE: Few techniques for targeted gene therapy are available, especially in deep tissues such as the kidney. This project will examine the ability of a targeted ultrasound-basedtechnique to deliver a therapeutic siRNA to diabetic kidney, and determine whether this strategy is able to ameliorate glomerular fibrosis in animal models of the disease.

* Information listed above is at the time of submission. *

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